Di(2-ethylhexyl) Phthalate Report on Carcinogens, Thirteenth Edition CAS No. 117-81-7

Report on Carcinogens, Thirteenth Edition
For Table of Contents, see home page: http://ntp.niehs.nih.gov/go/roc13
Di(2-ethylhexyl) Phthalate
Property
CAS No. 117-81-7
Reasonably anticipated to be a human carcinogen
First listed in the Third Annual Report on Carcinogens (1983)
Also known as DEHP, diethylhexyl phthalate, or dioctyl phthalate
O
C
C
O
H2
C
O
O
CH
H2C
H2C
C
H2
CH
H2
C
C
H2
H2
C
CH3
CH3
C
H2
C
H2
Information
390.6
0.986 at 20°C/20°C
–55°C
384°C
7.6
0.27 mg/L at 25°C
1.42 × 10–7 mm Hg at 25°C
Source: HSDB 2010.
CH3
H2
C
Molecular weight
Specific gravity
Melting point
Boiling point
Log Kow
Water solubility
Vapor pressure
CH3
Carcinogenicity
Di(2-ethylhexyl) phthalate (DEHP) is reasonably anticipated to be
a human carcinogen based on sufficient evidence of carcinogenicity
from studies in experimental animals.
Cancer Studies in Experimental Animals
Dietary exposure to DEHP caused benign and/or malignant liver tumors (hepatocellular adenoma and/or carcinoma) in mice and rats of
both sexes, and the tumor incidences showed significant dose-related
trends in both species (NTP 1982).
Since DEHP was listed in the Third Annual Report on Carcinogens, additional studies in rodents have been identified, which confirmed that DEHP caused liver tumors in rats and mice. DEHP also
caused liver tumors in PPARα-null mice, which lack the peroxisome
proliferator-activated receptor α (which has been proposed to be involved in DEHP-induced tumorigenesis) (Ito et al. 2007). In addition,
dietary exposure to DEHP caused benign testicular tumors (Leydigcell tumors) (Voss et al. 2005) and benign pancreatic tumors (acinarcell and islet-cell adenoma) in male rats (Rao et al. 1990, David et al.
2000). Initiation-promotion studies in two strains of mice provided
evidence that DEHP acted as a promoter of liver tumors (IARC 2000).
Cancer Studies in Humans
The data available from epidemiological studies are inadequate to
evaluate the relationship between human cancer and exposure specifically to DEHP (IARC 1982).
Properties
DEHP is a phthalate ester that exists as a colorless oily liquid with
a slight odor. It is slightly soluble in water and carbon tetrachloride, miscible with mineral oil and hexane, and soluble in blood and
body fluids containing lipoproteins. When heated to decomposition,
it emits acrid smoke. DEHP is incompatible with nitrates, strong
oxidizers, acids, and alkalis (HSDB 2010). DEHP is available in the
United States in a variety of technical grades. Typical product specifications include 99.0% to 99.6% minimal ester content, 0.1% maximal moisture content, and 0.007% to 0.01% acidity (as acetic acid
or phthalic acid) (IARC 2000). Physical and chemical properties of
DEHP are listed in the following table.
National Toxicology Program, Department of Health and Human Services
Use
About 95% of DEHP produced is used as a plasticizer in polyvinyl
chloride (PVC) resins for fabricating flexible vinyl products (ATSDR
2002). Products typically contain from 1% to 40% DEHP; however,
Tickner et al. (2001) reported that DEHP levels in PVC medical tubing may be as high as 80%. Plasticized PVC has been used in many
consumer items and building products, such as tablecloths, shower
curtains, furniture and automobile upholstery, imitation leather, garden hoses, floor tiles, swimming-pool liners, sheathing for wire and
cable, rainwear, shoes, toys, dolls, baby pants, food packaging materials, tubing used in commercial milking equipment, and weather
stripping (IARC 2000, ATSDR 2002, Bizzari et al. 2007). DEHP is also
used in medical devices (blood and intravenous solution bags, catheters, tubing for dialysis and parenteral solutions, oxygen masks, and
urine and colostomy bags) and in disposable surgical gloves. It has
been used as a plasticizer in non-PVC materials, including polyvinyl
butyral, natural and synthetic rubber, chlorinated rubber, ethyl cellulose, and nitrocellulose. In 2005, the breakdown of U.S. consumption
of DEHP as a plasticizer was reported to be 40% for medical devices,
30% for consumer goods, and 30% for construction-related applications (Bizzari et al. 2007).
Non-plasticizer uses of DEHP include its use in dielectric fluids
for electric capacitors, as an acaricide in orchards, as an inert ingredient in pesticides, in cosmetic products, as a vacuum-pump oil, to detect leaks in respirators, and in testing air-filtration systems. However,
some of these applications are believed to be no longer in use or were
never carried out on a commercial scale (IARC 2000, ATSDR 2002).
Historically, DEHP constituted about 50% of all the phthalate ester plasticizers used (IPCS 1992). However, the use of DEHP in some
products has diminished because of health concerns and regulatory
limitations on its use (ATSDR 2002, HCWH 2002). Furthermore,
DEHP is being replaced by linear phthalates and other plastomers in
many other applications, because of their superior performance and
low toxicity (ATSDR 2002). In the United States, DEHP constituted
roughly 10% of all plasticizers consumed in 2005; this was the smallest percentage of the total DEHP demand among the major world
regions (compared with 18% in Western Europe, 52% in Japan, and
62.4% in “Other Asia”).
Production
DEHP was first produced in the United States in 1939. Annual U.S.
production remained fairly steady from 1975 to 2003, ranging from a
peak of 180,000 metric tons (397 million pounds) in 1976 to a low of
109,000 metric tons (240 million pounds) in 1993. Total U.S. phthalate production in 2005 (the last year for which production data were
available) was 88,000 metric tons (194 million pounds), accounting
for 14.5% of total phthalate plasticizer production (Bizzari et al. 2007).
In 2010, DEHP was produced by two U.S. companies (SRI 2010) and
was available from 109 suppliers worldwide, including 45 U.S. suppliers (ChemSources 2010). In 2009, U.S. imports and exports of di-
Report on Carcinogens, Thirteenth Edition
octyl orthophthalates totaled 6,896 metric tons (15.2 million pounds)
and 3,630 metric tons (8 million pounds), respectively (USITC 2010).
Exposure
The primary routes of potential human exposure to DEHP are ingestion, inhalation, and through medical procedures; exposure levels are
highest for medical procedures (ATSDR 2002, NTP 2006). Dermal
absorption is another potential exposure route; however, dermal absorption of DEHP in vitro is low (IARC 2000).
Individuals receiving treatment with medical products containing DEHP are at risk for high DEHP exposure; exposure of newborn
infants is of particular concern. For both adults and neonates, the
highest estimated daily exposure levels were for blood transfusion,
at 22.6 mg/kg of body weight for neonatal exchange transfusion and
8.5 mg/kg for transfusion in adult trauma patients. The U.S. Food
and Drug Administration expressed special concern about aggregate
exposure from repeated medical procedures, which often occurs in
neonatal intensive-care settings. Other medical procedures that can
result in DEHP exposure include hemodialysis, transfusion of platelets or plasma, pheresis, nasogastric feeding, and respirator use (FDA
2001). Long-term use of some procedures can result in significant
total DEHP exposure. DEHP has been measured in large-volume
parenteral formulations (i.e., fluids, nutrients, and electrolytes) and
in whole blood and plasma stored in flexible-PVC bags (FDA 2001,
ATSDR 2002). DEHP was found in condensate from respirator water
traps at concentrations of up to 4,100 mg/L (IARC 2000).
Exposure to DEHP or its metabolites may occur in utero. DEHP
and its major metabolite mono(2-ethylhexyl) phthalate (MEHP) were
detected in cord blood collected from 84 newborns in Italy (Latini et
al. 2003b), and MEHP was detected in 24% of 54 amniotic-fluid samples collected by amniocentesis (Silva et al. 2004).
A substantial fraction of the U.S. general population is exposed to
measurable levels of DEHP because of its widespread use in consumer
products and its presence in foods, beverages, and the environment.
For the general population, the most important route of exposure is
ingestion. DEHP has been found at low levels in packaged food as a
result of its use as a plasticizer in products that contact food during
its manufacture or storage (ATSDR 2002). DEHP has been detected
in fish and other seafood, cheese, margarine, eggs, meat, cereal, baby
food, milk, and infant formula. Because DEHP is lipophilic, higher
levels are expected in fattier foods than in less fatty foods. In colostrum or milk from 17 healthy mothers, DEHP was detected in 16 of
17 samples and MEHP in 2 of 17 samples (Latini et al. 2003a). It has
been estimated that more than 90% of daily intake of DEHP by noninfants is from dietary intake of food, water, and other beverages
(Clark et al. 2003b). Daily exposure of adults in the general population was estimated to range from 1 to 30 μg/kg of body weight (0.001
to 0.03 mg/kg) (NTP 2006). Exposure may be several times as high
in infants and toddlers, as a result of nondietary mouthing behaviors (e.g., chewing on soft-PVC plastic toys and ingesting household
dust), with ingestion of household dust accounting for about half of
total DEHP intake for infants (ATSDR 2002, Clark et al. 2003b). The
concentration of DEHP in house dust was associated with the use of
PVC-based flooring and wall coverings in the home; however, DEHP
was also found in buildings that did not use PVC flooring or vinyl wall
coverings (Bornehag et al. 2005). Based on limited data, concentrations of DEHP in house dust are expected to range from a few hundred to several thousand parts per million (IARC 2000, ATSDR 2002,
Clark et al. 2003a, Rudel et al. 2003). Soft-PVC children’s toys may
contain DEHP, and children may ingest DEHP by sucking or chewing
National Toxicology Program, Department of Health and Human Services
on the toys. DEHP was the most common plasticizer used in pacifiers
and teethers until the early 1980s, when manufacturers voluntarily
agreed to eliminate its intentional addition (ATSDR 2002). However,
a study published in 2005 found that 12 of 18 such children’s products contained DEHP at levels ranging from 20 to 840 ppm, including a teething ring that contained 410 ppm (Hileman 2005).
DEHP is considered a ubiquitous environmental contaminant and
has been measured in outdoor and indoor air, water, sediment, and
soil (IARC 2000, ATSDR 2002). DEHP is released to the environment
from industrial facilities and waste-treatment plants. According to
the U.S. Environmental Protection Agency’s Toxics Release Inventory,
environmental releases of DEHP declined steadily from 4.9 million
pounds in 1988 to 1.5 million pounds in 1997 and have since leveled
off, with only minor variation from year to year. In 2008, releases of
DEHP totaled around 960,000 lb (TRI 2010). In air, DEHP is expected
to react with hydroxyl radicals, with an estimated half-life of about
6 hours. However, the expected adsorption of most DEHP to atmospheric particulates will decrease the reaction with hydroxyl radicals, resulting in a potentially longer atmospheric half-life. DEHP is
readily removed from the atmosphere by rain or snow (ATSDR 2002).
DEHP in indoor air is due primarily to volatilization from consumer products and building materials that contain DEHP. In general, concentrations are expected to be higher in indoor air than in
outdoor ambient air (ATSDR 2002). DEHP has also been measured
at high air concentrations in cars. Some studies have suggested that
because of DEHP’s tendency to adsorb to airborne particulates, levels estimated based only on gas-phase measurements might underestimate total air levels. It was suggested that exposure to DEHP from
indoor air may increase by a factor of up to three when particulatematter contributions are accounted for (Øie et al. 1997).
DEHP has been detected in drinking water, surface water, groundwater, rainwater, and seawater, generally in the low parts-per-billion
range. In water, DEHP is expected mainly to adsorb to suspended
particulates; its evaporation from water is expected to be negligible
(ATSDR 2002). However, its degradative half-life has been estimated
to be roughly 10 hours in river water and 2 weeks in river sediment
(Yuwatini et al. 2006). The main sources of DEHP released to land
and soil are disposal of industrial and municipal waste to landfills
and land application of DEHP-containing sludges (e.g., industrial or
sewage sludges). Disposal of products containing flexible PVC, such
as food wraps, may be a source of DEHP in municipal waste (IARC
2000). DEHP adsorbs strongly to soil, thus limiting losses from volatilization or leaching; however, co-disposal with common organic
solvents could increase its solubility and its mobility in soil.
Air concentrations of DEHP in occupational settings (i.e., industrial production) may be significantly higher than general indoor levels. Occupational exposure to DEHP occurs primarily among workers
involved in the manufacture and processing of DEHP and flexiblePVC plastics and plastic products, with inhalation of aerosols or mists
the major route of exposure (IARC 2000, ATSDR 2002). DEHP is easily released into air at typical PVC-processing temperatures (Vainiotalo and Pfaffli 1990). However, few data are available on occupational
exposure to DEHP. Air exposure levels of DEHP were reported to
range from below the limit of detection to 4.1 mg/m3 across various processes at a U.S. production facility. Higher urinary levels of
DEHP, its metabolites, and total phthalates have been measured in
DEHP-exposed workers than in non-exposed workers and in postshift samples than in pre-shift samples (IARC 2000).
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Report on Carcinogens, Thirteenth Edition
Regulations
Consumer Product Safety Commission (CPSC)
A voluntary standard provides that pacifiers, rattles, and teethers shall not intentionally contain DEHP.
It is unlawful for any person to manufacture for sale, offer for sale, distribute in commerce, or import
into the United States any children’s toy or child-care article that contains DEHP at concentrations
of more than 0.1%.
Environmental Protection Agency (EPA)
Clean Air Act
National Emission Standards for Hazardous Air Pollutants: Listed as a hazardous air pollutant.
New Source Performance Standards: Manufacture of DEHP is subject to certain provisions for the control
of volatile organic compound emissions.
Clean Water Act
Effluent Guidelines: Phthalate esters are listed as toxic pollutants.
Water Quality Criteria: Based on fish or shellfish and water consumption = 1.2 μg/L; based on fish or
shellfish consumption only = 2.2 μg/L.
Comprehensive Environmental Response, Compensation, and Liability Act
Reportable quantity (RQ) = 100 lb.
Emergency Planning and Community Right-To-Know Act
Toxics Release Inventory: Listed substance subject to reporting requirements.
Resource Conservation and Recovery Act
Listed Hazardous Waste: Waste code for which the listing is based wholly or partly on the presence of
DEHP = U028.
Listed as a hazardous constituent of waste.
Safe Drinking Water Act
Maximum contaminant level (MCL) = 0.006 mg/L.
Food and Drug Administration (FDA)
Limitations on the use of DEHP in basic components of single and repeated use food contact surfaces
are prescribed in 21 CFR 177.
Occupational Safety and Health Administration (OSHA)
While this section accurately identifies OSHA’s legally enforceable PELs for this substance in 2010,
specific PELs may not reflect the more current studies and may not adequately protect workers.
Permissible exposure limit (PEL) = 5 mg/m3.
Guidelines
American Conference of Governmental Industrial Hygienists (ACGIH)
Threshold limit value – time-weighted average (TLV-TWA) = 5 mg/m3.
National Institute for Occupational Safety and Health (NIOSH)
Immediately dangerous to life and health (IDLH) limit = 5,000 mg/m3.
Recommended exposure limit (time-weighted-average workday) = 5 mg/m3.
Short-term exposure limit (STEL) = 10 mg/m3.
Listed as a potential occupational carcinogen.
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